Diabetes mellitus is an epidemic disease that is the fourth leading cause of death worldwide, the leading cause of kidney disease in developed countries and the leading cause of blindness in industrialized nations. In 2007, $174 billion of cost was attributed to the disease from lost productivity and health-care related expense. The most prevalent form, type 2 diabetes, targets multiple organs and is a progressive disease, requiring additional treatment and expense as it progresses. Therefore, new and differentiated treatment options represent a major unmet medical need. One major recent therapeutic advance targets the incretin axis, and therapies that either directly provide additional glucagon like peptide-1 (GLP-1) through administration of stable GLP-1 analogs or prevent the degradation of naturally produced GLP-1 via the inhibition of degradative, protelytic enzymes such as dipeptidyl peptidase IV (DPP4). In turn, GLP-1 can modulate insulin secretion resulting in enhanced insulin secretion and glucose uptake.
Bile acids play essential roles in the absorption of dietary lipids and in the regulation of bile acid biosynthesis. While bile acids have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for bile acids as signaling molecules has emerged. Bile acids are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor a (FXR-a). Through activation of these diverse signaling pathways, bile acids can regulate their own enterohepatic circulation, but also triglyceride, cholesterol, energy, and glucose homeostasis. Thus, bile acid (BA) controlled signaling pathways are promising novel drug targets to treat common metabolic diseases, such as obesity, type II diabetes, hyperlipidemia, and atherosclerosis.
The receptor commonly referred to as TGR5 (also known as GPBAR1, BG37, AXOR109, GPCR19, and GPR131) has been shown to respond to bile acids, and thus is postulated to mediate the recently discovered signaling properties attributed to these molecules. The membrane-bound receptor is highly expressed in the gall bladder, but also throughout the intestinal tract, and has also been reported in myocytes, monocytes/macrophages as well as other tissues and organs. The TGR5 receptor is known to be coupled to the Gs type G protein which activates cAMP biosynthesis, which in turn is thought to mediate some or all of the TGR5-mediated biologic actions.
Glucagon-like peptide-1 (GLP-1) is produced by L-cells in the distal digestive tract and affects multiple metabolic parameters, including enhanced insulin secretion, glucagon suppression, and lowering of blood glucose. Modulation of the TGR5 receptor has been proposed to result in the stimulation of GLP-1 secretion in the gastrointestinal tract, which upon acting on the pancreatic beta cell could then result in additional glucose-stimulated insulin secretion (GSIS). TGR5 receptor signaling has also been suggested to increase oxidative phosphorylation and energy metabolism in muscle and mediate anti-inflammatory actions at other sites of diabetic injury, which together or separately may hold potential benefits for treatment of the disease. Administration of bile acids to mice has also been reported to increase energy expenditure, thereby preventing obesity and insulin resistance. This novel metabolic effect of bile acids is thought to be dependent on induction of type 2 iodothyronine deiodinase (D2) and conversion of T4 to T3, because it is absent in D2−/− mice.
Accordingly, compounds that activate TGR5, alone or in combination with other medicaments, could demonstrate a wide range of utilities in treating inflammatory, allergic, autoimmune, metabolic, cancer and/or cardiovascular diseases, in particular diabetes mellitus. PCT Publication Nos. WO 2010/093845 A1, WO 2011/071565 A1, WO 2010/059859 A1, WO 2010/016846 A1, WO 2009/026241 A1, WO 2008/067222 A1, WO 2008/097976 A1 and WO 2008/067219 A2, disclose compounds that activate TGR5 and methods of treating diseases associated with TGR5. The references also disclose various processes to prepare these compounds.